AT393123B - METHOD FOR PRODUCING NEW -ARYL-5H-2,3-BENZODIAZEPINE DERIVATIVES AND THEIR ACID ADDITION SALTS - Google Patents

Description

AT 393 123 B

The invention relates to a process for the preparation of new 1-aryl-5H-23-benzodiazepine derivatives of the general formula (I),

in which R and Rj independently of one another are a hydrogen atom or chlorine atom, an alkyl group with 1-4 C atoms or alkoxy group with 1-4 C atoms, R2 is a hydrogen atom or an alkyl group with 1-4 C atoms,

Rj and R4 can denote an alkyl group with 1-4 C atoms and R3 and R4 together can denote a methylene group, as well as their acid addition salts.

The range of pharmacological effects of the 5H-2,3-benzodiazepine derivatives known from the specialist literature (US Pat. Nos. 3,736,315 and BE-PS 879,404) is different from that of 1,4-benzodiazepines, u. It is much more advantageous because the compounds have no spasmolytic effect and do not cause muscle weakness or coordination disorders.

The new 1-aryl-5H-23-benzodiazepine derivatives of the general formula (I) have a significant influence on the central nervous system and have mainly anti-aggressive and anxiolytic effects. Their potency is several times greater than that of the commercial preparation tofisopam (grandaxin = 1- (3,4-dimethoxyphenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5ii-23-benzodiazepine), as well as that of l- (3rd -Chlorphenyl) -4-methyl-7,8-dimethoxy-5 £ -2,3-benzodiazepine (U.S. Patent 4,322,346). While the known compounds generally have an anti-depressive character in addition to their anxiolytic activity, the compounds of the general formula (I) are also mild neuroleptics. Thus, the last-mentioned compounds are suitable as active ingredients of day sedatives for the treatment of anxiolytic and stress conditions. The compounds of the general formula (I) are prepared according to the invention in that a nitro compound of the general formula (IQ,

wherein R, R}, R2, R3 and R4 have the above meaning, is reduced in an organic solvent, and, if desired, an acid addition salt is formed from the base of the general formula (I) obtained, if desired the free base is then formed released their salt according to a known method and -2-

AT 393 123 B is converted into another acid addition salt using an acid.

Alcohols with 1 * 4 carbon atoms, dioxane, tetrahydrofuran, benzene, toluene, xylene, dimethylformamide, dimethylacetamide or mixtures thereof can be used as organic solvents.

According to an advantageous embodiment of the process according to the invention, a nitro compound of the general formula (Π) is dissolved in dimethylformamide and catalytically hydrogenated.

The hydrogenation can preferably be carried out at room temperature. Palladium-activated carbon, platinum or Raney nickel are used as catalysts.

The reaction mixture is worked up using a known method. The catalyst is filtered, the solvent is evaporated in vacuo, and the residue is purified by means of precipitation, recrystallization and / or digesting. Lower alcohols are preferred recrystallization agents.

Under the above circumstances, only the nitrogne is reduced in the catalytic hydrogenation of the 5H-2,3-benzodiazepine derivatives of the general formula (II), while in the 1,4-benzodiazepines the similarly positioned C = N double bond is saturated with catalytic hydrogenation can become [J. Org. Chem. 2 > 2456 (1963); Coli. Czech. Chem. Comm. 2L 1264 (1966)].

According to a further advantageous embodiment of the process according to the invention, a nitro compound of the general formula (Π) is suspended in a lower alcohol and reduced in the presence of a catalyst with hydrazine or hydrazine hydrate. In the reaction, 98-100% hydrazine hydrate and, as catalyst, palladium- Activated carbon, platinum or Raney nickel are used. The reduction is carried out in a temperature range between 20 ° C. and the boiling point of the solvent, preferably at room temperature. The reaction mixture is worked up according to a known method, as above

The reduction carried out with hydrazine hydrate is particularly favorable for those compounds which have a chlorine substituent [Chem. Rev. öö, 51 (1965)]. All other reduction methods which do not cause any change in the structure of the diazepine ring itself are suitable for the reduction of the nitro compounds of the general formula (Π). No complex metal hydrides can be used for the reduction, since this leads not only to the reduction of the nitro group, but also to the saturation of the C = N double bond in the diazepine ring between the nitrogen atom in position 3 and the carbon atom in position 4 (US Patent No. 4,423,044). In zinc dust reduction in glacial acetic acid, a 6-membered ring is formed from the 7-membered ring of the 5H-2,3-benzodiazepine derivatives by releasing one mole of ammonia, which gives isoquinoline derivatives [Chem. Ber. 107.3883 (1974)].

In the process according to the invention, the compounds of the general formula (I) are obtained in base form. For the preparation of acid addition salts of the compounds of the general formula (I), the base is preferably dissolved or suspended in a suitable solvent, for example in methanol, ethanol, isopropanol, glacial acetic acid or water, then with an appropriate acid, for example hydrochloric acid, bromohydrogenic acid, Phosphoric acid, sulfuric acid or with a solution thereof. The salts can be obtained directly by filtration or after evaporation of the solvent.

Some crude bases cannot be purified by direct recrystallization, they are preferably released from their pure acid addition salts formed according to the above procedure. For the release of the bases of the general formula (I) their corresponding salts are dissolved in a solvent, for example in water, the solution is either with an organic base, for example with triethylamine or pyridine, or with an inorganic base, for example with an aqueous sodium hydroxide or ammonium hydroxide solution is added, and the base released is filtered. If desired, an acid addition salt is formed from the pure base obtained by the above method using an appropriate acid.

The compounds of the general formula (Π) used as starting materials in the process according to the invention are partly new and partly known substances. They can preferably be obtained from the corresponding pyrylium salts or from 1,5-diketones with hydrazine or hydrazine hydrate (Belgian patent No. 879 404).

The compounds of the general formula (I) obtainable according to the invention have a significant influence on the central nervous system and have valuable antiaggressive, anxiolytic, anesthetic-potentiating and hypnotic effects, and they also inhibit psychomotor hyperactivity.

The anti-aggressive effect was examined with the " fighting behaviorVTest [J. Pharm. Exp. Ther. 125, 28 (1959)]. Tofisopam and l- (3-chlorophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine served as reference substances. The test results were summarized in Table 1.

Continuation of table 1 -3-

AT 393 123 B labglfri

Investigation of the anti-aggressive effect in the mouse with the "fighting behavior" test

Substance ED ^ g- Value Relative (Example No.) mg / kg p.o. Activity 1 8.1 7.9 2 12.5 5.1 10 9.1 7.0 11 16.0 4.6 15 17.0 3.8 18 7.9 8.1

Tofisopam 74.0 1.0 l- (3-Chloq) henyl) -4-methyl-7,8-di-16,0 4,6 methoxy-5H-2,3-benzodiazepine

The anxiolytic effect was examined with the "Lick-conflict" test according to Vogel IPsychopharmacoL 21.1 (1971)]. Tofisopam, 1- (3-chlorophenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine and chlorodiazepoxide (7-chloro-2-methylamino-5-phenyl-3Ii, -1, 4-benzodiazepine -4-oxide) served as reference substances. The test results were summarized in Table 2.

Table 2

Studies of the anxiolytic effect on the rat using the " lick conflict test

Substance Example No. Dose mg / kg i.p. N Number of animals Number of tolerated electric shocks ± SE significance vehicle - 6 2.3 ± 0.4 1 2.5 10 4.1 ± 0.7 unsignificant vehicle - 23 2.8 ± 0.3 1 5 22 13.9 ± 2.7 p < 0.001 vehicle - 20 4.4 ± 0.7 1 10 21 19.7 ± 2.9 p < 0.001 vehicle _ 5 33 ± 0.6 2 10 10 43 ± 0.7 insignificant vehicle - 10 5.5 ± 1.1 2 25 17 15.1 ± 1.9 p < 0.001 vehicle 8 3.3 ± 0.5 18 23 8 7.6 ± 3.0 insignificant vehicle - 15 4.9 ± 034 18 5 20 8.3 ± 1.0 p < 0.05 vehicle m 60 4.5 ± 0.4 tofisopam 25 10 3.6 ± 0.4 insignificant 50 16 19.8 ± 3.7 p < 0.001 chlorodiazepoxide 5 10 9.7 ± 3.7 insignificant 10 24 27.5 ± 2.5 p < 0.001 l- (3-chloro-25 13 9.9 ± 2.8 iffl significant phenyl) 4- 50 -methyl-7,8-dimethoxy - 5H-23-benzodiazepine 24 19.0 ± 2.3 p < 0.001 -4-

AT 393 123 B

The spontaneous motor activity was determined with a Animex-type motimeter. After 24 hours of fasting, 3 CFLP mice (20-23 g in weight) were placed in the apparatus, and after 10 minutes of oral pretreatment, the activity of the animals was measured continuously for 2 hours. The dose was determined which reduced the spontaneous motor activity of the animals by half compared to the control group treated with vehicle only. The ED ^ values were calculated using the method of Litchfield and Wilcoxon [J. Pharmacol. Exp. Ther. 26.99 (1949)] and some are summarized in Table 3

Tahelkä

Determination of spontaneous motor activity

Substance Example No. EDsQ value mg / kg p.o. 1 3.2 (1.8-5.9) 2 1.3 (0.6-2.8) 8 48.0 (37.8-61.0) 10 4.4 (3.7-53) 15 9.7 (6.7-14.1) tofisopam 1- (3-chlorophenyl) -4-methyl-7,8-dimethoxy-22.0 (16.4-293) -5fi-2,3-benzodiazepine 63 (4.0-9.7)

The anesthetic potentiation study of each compound was carried out in groups of mice, each with 15-20 animals, with 3-4 oral doses. The ED ^ Q value is the dose which in half of the animals doubles the anesthetic time caused by an intravenous 50 mg / kg dose of hexobarbital sodium

Table 4

Naicosis potentiation in the mouse

Compound Example No.ED50 mg / kg p.o. 1 4.8 (3.4-6.6) 2 83 (5.4 -12.5) 8 7.4 (4.8-11.3) 10 7.4 (5.6-9.7) 15 25 (183 * 343) 18 7.6 (5.5-10.4) tofisopam 38 l- (3-chlorophenyl) -4-methyl-7,8-dimethoxy-51i-23-benzodiazepine 16

The experimental results summarized in the tables show that several compounds achieve or significantly exceed the effectiveness of the reference substances, the most effective of which are the 1- (4-aminophenyl) -4-methyl-7,8-dimelhoxy-5H-2,3 -benzodiazepffi (compound from Beispei 1) and the l- (3-Chl (u4-aminophenylH-methyl-7,8-dimethoxy-5H-23-benzodiazepine (compound from Beispei 18).

The 1- (4-aminophenyl) -4-methyl-7,8-methylenedioxy-5S-23 * benzodiazepine (compound of Example 8) has significant hypnotic activity. Its HDjQ values in the mouse are 140 mg / kg po “70 mg / kg ip, -5-

AT 393 123 B 40 mg / kg IV, and on the rat 40 mg / kg IV. The HDjQ values of the nitrazepam (7-nitro-5-phenyl-l, 3-dihydro-2H-l, 4-benzodiazepin-2-one) on the mouse are 185 mg / kg po, 150 mg / kg ip, 76 mg / kg Lv. and on the rat 96 mg / kg IV

Those compounds of the general formula (I) in which R 1 and R 4 together represent a methylene group, in contrast to the other compounds of the general formula (I), also have significant muscle relaxant and spasmolytic effects. For example, l- (4-aminophenyl) 4-methyl-7,8-methylenedioxy-5II-23-benzodiazepine (compound from Example 8) is a muscle relaxant with a central point of attack and is much more effective than the reference compound zoxazolamine (2-amino-5 -chloro-1,3-benzoxazole). Their ED ^ q values are 47 and > 100 mg / kg i.p. in the "inclined screen" test (J. Pharm. Exp. 129.163 [I960]) and 24 or 74 mg / kg i.p. in the Rotarod test (J. of Am. Pharm. Assoc. 46,208 [1957]).

The new compounds form the basis for pharmaceutical compositions which contain at least one compound of the general formula (I) as active ingredient, together with one or more customary auxiliaries, and also carriers, diluents and / or additives. If desired, the pharmaceutical compositions can also contain other active ingredients. The pharmaceutical compositions can be produced using conventional methods known per se. A daily human dose of 25-75 mg of the compound obtainable according to the invention is provided for therapeutic purposes.

The invention is explained in more detail using the examples below, without restricting the scope of protection to these examples.

Example 1 l-f4-Ammophenv04-methvl-7.8-dimethoxv-5H-2.3-benzndia7.epin

A suspension of 26.6 g (0.078 M) of 1- (4-nitrophenyl) 4-methyl-7,8-dimethoxy-5H * 2,3-benzodiazq) in 540 ml of dimethylformamide is mixed with a suspension of 2 g of 10% palladium-activated carbon catalyst in 60 ml of dimethylformamide, and the mixture is stirred in a hydrogen atmosphere at room temperature. The reduction will be complete in about 15 hours. Then the catalyst is filtered, the filtrate is treated with activated carbon and evaporated in vacuo. The crystal residue is heated under reflux with 250 ml of ethanol for one hour. After cooling, the crystals are filtered, washed twice with 30 ml of ethanol each time and dried at 80-100 ° C. Yield: 21.5 g (89%), mp. 225-227 ° C. C18H19N3 ° 2 = 309,374

Production of the hydrochloride salts:

A calculated amount of absolute alcohol saturated with HCl gas is added to a solution of 1 g base in 5 ml glacial acetic acid. The crystals which have separated out are filtered and washed with ethyl acetate. Monohydrochloride: [CigHjQNgC ^ lCl = 345.839,

237-238 ° C (dec.).

Calculates CI 10.25%. Found: Q 10.4%

Dihydrochloride: [Cjg ^ iN ^ C ^ C ^ = 382,304 mp 236-238 ° C (dec.).

Calculates CI 18.55%. Found: CI 18.3%.

Preparation of the sulfate:

The aqueous solution of 1 g base is with the calculated amount of cc. Sulfuric acid and after evaporation of the solution the residue is processed with hot isopropanol. The crude product is recrystallized from glacial acetic acid tc18H20N3 ° 2] 2SO4 * 716.830, mp. 235-237 ° C (dec.).

Calculates SO413.4%. Found: SO413.55%.

The compounds of Example 2-7 are also prepared using the process of Example 1 50% ethanol).

Monohydrochloride: [CigH2QN302] Cl = 345.839 mp 195-198 ° C (dec.).

Dihydrochloride: [C18H21N302] C1 = 382304

Mp 217-218 ° C (dec.) (From isopropanol). -6-

AT393 123 B

Example 3 1- (2-aminophenvD4-methvl-7.8-dimethoxv-5H-2.3-benzodiazepine

Mp 172-174 ° C (from a mixture of dimethylformamide and water, then suspended in ethanol).

Dihydrochloride: mp 174-176 ° C (dec.) (From isopropanol). 5

Example 4 l- (3-AminoohenvlV4-methvl-7.S-Hiathn > v-5H-2 3-hen7Jvtia7flnin

M.p. 133 -134 ° C (from a mixture of ethanol and water). 10 Example 5 l-f3-aminophenv0-4-methvl-7.8-methvlenendioxy-SH-2.3-hen7ndia7epin

Mp 190-191 ° C (from a mixture of ethanol and water).

Example 6 15 l- (2-Amino4.5-dimethoxvphenyl) 4-methvl-7.8-dimethoxy-5H-2.3-benzodiazepine

194 -196 ° C (from a mixture of dimethylformamide and water).

Example?. ! - (, 2-aminophenvr) -4-methyl-7.8-methylenedioxv-5H-23-ben7 / vtia7flpin 20 mp. 171 - 173 ° C (from ethanol).

Example 8 l-f4-AminophenyD-4-methvl-7.8-methvlendioxv-5H-2.3-benzoriia7.ftpin

The suspension of 142 g (0.0047 M) 1- (4-nitrophenyl) -4-methyl-7,8-methylenedioxy-5Il-23-benzocliazepine 25 in 45 ml methanol is mixed with 0.2 g 10% palladium- Activated carbon catalyst and 0.7 ml (0.014 M) 100% hydrazine hydrate are added, the reaction mixture is stirred for 6 hours at room temperature, then heated to 50-60 ° C., the catalyst is filtered and washed three times with 10 ml of methanol. The filtrate is evaporated in vacuo, and the residue is recrystallized from 5 ml of 99.5% ethanol. Yield: 1.05 g (76%), mp. 198-199 ° C. 30 Using the procedure of Example 8, the compounds of Example 9-12 are prepared. The reaction solvents used are methanol, ethanol or dioxane, and the reduction is also carried out at the boiling point of the solvents

Example 9 35 l-f2-Amino-5-chlorophenvr > -4rmethvl-7-8-dimethoxv-5H-2.3-benzoriiazepine

Mp 190-192 ° C (suspended in ethanol).

Example 10 l- (3-Methvl - 4-aminophenvl) 4-methvl-7.8-dimethoxy-5H-23-benzodiazepine 40 mp 192-194 ° C (from isopropanol).

Example 11 1- (4-aminophenvl) 44-dimethvl-7.8-dimethoxv-5H-2-3-hen7odia7enin

M.p. 188-190 ° C (suspended in ethanol). 45

Example 12 l-f4-aminophenvf> -4-methvl-5-ethvl-7-8-dimethoxv-5H-2.3-benzodiazepine

M.p. 166 -168 ° C (from the dihydrochloride in aqueous »: solution released). 50 Example 13 l-f2-Qil (y-4-aminophenvl) -4-methvl-7.8-dimethoxv-5H-2.3-benzodiazepine

A mixture of 4.10 g (0.011 M) of 1- (2-chloro-4-nitro-phenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine, 100 ml of methanol, 0 , 4 g of Raney nickel catalyst and 13 ml (0.025 M) of 98% hydrazine hydrate are stirred for one hour. The reaction mixture »warms up to 40 - 45 ° C, then cools down to room temperature. After completion of the reduction, the mixture is heated to 40-45 ° C., the catalyst is filtered and washed twice with 10 ml of chloroform each time, then the filtrate is evaporated in vacuo. The residue is refluxed for 2 hours with 20 ml of ethanol: first a solution formed then prompt crystallization sets in. After cooling, the crystals are filtered, washed three times with 3 ml of ethanol each time and at 60-100 ° C until reached »! of constant weight dried -7-

AT 393 123 B

Yield: 33 g (87%).

Mp 218-220 ° C (dec.).

The compounds of Example 14-18 were prepared using the procedure of Example 13, with the difference that ethanol, isopropanol or dioxane is used instead of methanol, and the reduction S is carried out at a higher temperature.

Example 14 l-f3-Amino4-chlorothenvlU-methvl-7.8-dimethoxv-5H-23-be-n7odiazenin

Mp 214-21 ° C. (dec.) (From a mixture of dimethylformamide and water, then suspended in ethanol 10).

Example 15 l- (3-Amino4-methvlDhenvl ') 4-methvl-7.8-dimethoxv-5H-2.3-benzodia7fipin mp 197-199 ° C (dec.) (Suspended in ethanol). 15

Example 16 H- (2-Chloro-5-aminophenvlV4-methvl-7.8-dimethoxv-5H-2.3-ben7ndiazfipin

Mp 188-190 ° C (from a mixture of dimethylformamide and water, then suspended in ethanol). 20 Example 17 l- (4-AmmophenvD-4-methvl-7.8-diethoxv-5H-2.3-lvM7Pdia7finin

M.p. 133 -135 ° C (from ethanol).

Example 18 25! - (3-Qilor-4-aminophenvlV4-methvl-7.8-dimethoxv-5H-2.3-lv > n7r) dia7spin

Mp 173-175 ° C (suspended in ethanol).

Instructions for a composition for the production of tablets 30 tablets, which contain 20 ml of l- (4-aminophenyl) -4-methyl-7,8-dimethoxy-5E-2,3-benzodiazepine as the active ingredient, can be used with conventional known methods can be produced. Their composition is as follows:

Active ingredient 20.0 mg 35 lactose 122.0 mg corn starch 203 mg cellulose (microcrystalline) 10.0 mg gelatin 3.5 mg talcum 2.0 mg 40 stearin 1.0 mg magnesium stearal 10 mg 180.0 mg

Continued claims 45 50 55 -8- 60

Claims (1)

AT393 123 B PATENT CLAIM Process for the preparation of new l-alyl-5ü-23-benzodiazepine derivatives of the general formula (I), .0) wherein R and Rj independently of one another are a hydrogen atom or chlorine atom, an alkyl group with 1 to 4 C atoms or alkoxy group with 1 to 4 C atoms, R2 is a hydrogen atom or an alkyl group with 1 to 4 C atoms, Rg and R4 an alkyl group having 1 to 4 carbon atoms, and R3 and R4 together can denote a methylene group, and acid addition salts thereof, characterized in that a nitro compound has the general formula (Π), 0D in which R, Rj, R2, R3 and R4 have the above meaning, is reduced in an organic solvent, and, if desired, an acid addition salt is formed from the base obtained since the general formula (I), if desired, the free base is then removed their salt is released according to a known method and is converted into another acid addition salt by means of an acid. -9-